1. Field of the Invention
The invention concerns aminodesoxy-1.4;3.6-dianhydrohexitol nitrates of the general formula I, ##STR2## wherein R.sup.1 and R.sup.2, each independently of one another, signify a hydrogen atom or a lower alkyl group with 1 to 4 C-atoms or wherein R.sup.1 signifies a hydrogen atom or a lower alkyl group with 1 to 4 C-atoms and R.sup.2 an acyl radical of an aliphatic or singly unsaturated, possibly methyl-substituted monocarboxylic acid with 2 to 8 C-atoms, a nicotinoyl, 2-O-acetylsalicoyl radical or a 1-adamantyl radical, or wherein R.sup.1 signifies a hydrogen atom and R.sup.2 a 2-hydroxy-3-(subst.)-phenoxyprop-1-yl radical of the general formula Ia ##STR3## wherein R.sup.3 signifies a hydrogen atom, a lower alkyl or lower alkenyl group with 1 to 4 C-atoms, the trifluoromethyl radical, a hydroxyl group, a lower alkoxy or lower alkenyloxy group with 1 to 4 C-atoms, a cyano group or a carbamoylmethyl radical, or wherein R.sup.1 signifies a hydrogen atom and R.sup.2 a 2-hydroxy-3-(.alpha.-naphthyloxy)-prop-1-yl radical, whereby the ring of the naphthalene structure not etherified with the hydroxypropyl group can be wholly or partially hydrogenated or substituted by an oxo group, or wherein R.sup.1 signifies a hydrogen atom or a lower alkyl group with 1 to 4 C-atoms and R.sup.2 an .omega.-(subst.)-phenylalkyl group of the general formula Ib ##STR4## wherein n can be=a whole number from 1-6 and R.sup.4 and R.sup.5, each independently of one another, signify a hydrogen atom, a lower alkyl or alkenyl group with 1 to 4 C-atoms, the trifluoromethyl radical, a hydroxyl group, a lower alkoxy or lower alkenyloxy group with 1 to 4 C-atoms or a fluorine or chlorine atom, or wherein R.sup.1 signifies a hydrogen atom or a lower alkyl group with 1 to 4C-atoms and R.sup.2 the diphenylmethyl radical or cinnamyl radical, or wherein R.sup.1 signifies a hydrogen atom or a lower alkyl group with 1 to 4 C-atoms and R.sup.2 an .omega.-(subst.)-phenoxyalkyl group of the general formula Ic ##STR5## wherein m can be=a whole number of 2-8 and R.sup.6 and R.sup.7, independently of one another, a hydrogen atom, a lower alkyl or lower alkenyl group with 1 to 4 C-atoms, the trifluoromethyl radical, a hydroxyl group, a lower alkoxy or lower alkenyloxy group with 1 to 4 C-atoms, a fluorine or chlorine atom, the amino or acetylamino group, a mono- or di-lower alkylamino group with 1 to 4 C-atoms or R.sup.6 and R.sup.7, together with the phenyl radical, form the .alpha.-naphthyl radical, or wherein R.sup.1 and R.sup.2, together with the nitrogen atom to which they are attached, represent the radical of a cyclic, non-aromatic, secondary amine with 5 to 7 ring atoms, possibly containing a further hetero atom, or wherein R.sup.1 and R.sup.2 together signify the pyridoxylidene radical, as well as their pharmacologically acceptable acid-addition salts.
The basic structure of these compounds consists of one of the stereoisomeric 1.4;3.6-dianhydrohexitols, convertible into one another by epimerisation, namely, either 1.4:3.6-dianhydro-L-iditol (="isoidide") (II), ##STR6## in which the OH groups in the 2- and 5-position each have the exo-configuration, or 1.4;3.6-dianhydro-D-glucitol (="isosorbide") (III) ##STR7## which has a 2-exo-standing and a 5-endo-standing OH group and thus--in the case of different substituents in the 2- and 5-position--occurs in two isomeric forms.
Finally, the basic structure of some compounds consists of 1.4;3.6-dianhydro-D-mannitol (="isomannide") (IV), ##STR8## which has two endo-standing OH groups.
Since, in contradistinction to the glucitol derivatives, in the case of the iditol and mannitol derivatives a difference between the 2- and 5-substituents is not possible because the C.sup.2 -atom, in the case of rotation of the molecule through 180.degree., becomes the C.sup.5 -atom, references to the 5-position or 2-position of substituents are superfluous in the case of these compounds. However, for a better comparison of the structures of the individual compounds with the general formulae, the isoidide derivatives are here always referred to as 5-aminoisoidide derivatives since they result from the isosorbide derivatives acyl-substituted in the 5-position. Correspondingly, the isomannide acyl derivatives employed as starting compounds are referred to as 2-acylisomannide derivatives since they are prepared from isosorbide derivatives substituted in the 2-position.
2. Description of the Prior Art
A brief summary regarding the stereoisomerism of the 1.4;3.6-dianhydrohexitols is given by J. A. Mills in Advances in Carbohydrate Chem., 10, 1-53 (1955).
The invention also concerns processes for the preparation of the initially-mentioned aminodesoxy-1.4;3.6-dianhydrohexitol nitrates, as well as pharmaceutical compositions which contain the compounds according to the invention.
The nitrates of 1.4;3.6-dianhydro-D-glucitol (also called 1.4;3.6-dianhydro-D-sorbitol) are known e.g. from U.S. patent specification No. 3,886,186, namely, not only the 2- and 5-mononitrates but also the 2,5-dinitrates of isosorbide. These nitrates, especially the dinitrate, which are already commercially available as medicaments, are pharmacologically active substances with haemodynamic, vasodilatory and antianginous effectiveness which are especially employed in the case of coronary insufficiency and for the treatment of angina pectoris.
The pharmacokinetics of the dinitrate and of the mononitrates of isosorbide, isomannide and isoidide have been described by Bogaert and Rosseel in Naunyn-Schmiedeberg's Arch. Pharmacol., 275, 339 (1972).
However, it has been shown that the nitrates cause unpleasant side effects, especially headaches. Furthermore, the mononitrates are more poorly resorbed than, for example, isosorbide dinitrate (ISDN). It is also to be added that the dinitrates of isosorbide, isomannide and isoidide can only be prepared and handled with special precautionary measures because they are explosive.